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Objective: To determine if patterns of hypoxic-ischemic brain injury on magnetic resonance imaging (MRI) in term newborns predict subsequent childhood epilepsy. Methods: This retrospective cohort study includes term newborns with encephalopathy (n = 181) born between 2004-2012 and admitted to British Columbia Children’s Hospital. MRI was performed between 3 and 5 days of age. The predominant patterns of hypoxic-ischemic injury were classified as Normal, Watershed, Basal Nuclei, Total, and Focal-Multifocal. Lesions in hippocampus, motor and occipital cortex were noted. Results: Of 181 newborns, 166 (92%) survived the neonatal period, and 132 (80%) had follow-up with a median duration of 61 months (IQR: 28–95). Twenty-three children (17%) developed epilepsy. A higher proportion with Watershed, Basal Nuclei, or Total patterns developed epilepsy ( P < .001). Injury to motor cortex, hippocampus, and occipital lobe ( P < .01) were independent risk factors for epilepsy. In the adjusting logistic model, Watershed (odds ratio = 16.0, 95% CI [1.3, 197.2], P = .03) and Basal Nuclei injury (odds ratio = 19.4, 95% CI [1.9, 196.3], P = .01) remained independent risk factors. Therapeutic hypothermia did not alter these associations. Severity of brain injury and recurrent neonatal seizures are other clinical risk factors. Significance: In term newborns with hypoxic-ischemic encephalopathy, the predominant pattern of Watershed and Basal Nuclei injury are valuable predictors for development of epilepsy in later childhood.

BACKGROUND:Brain injury (BI) is reported in 60% of newborns with critical congenital heart disease as white matter injury (WMI) or stroke. Neurodevelopmental (ND) impairments are reported in these patients. The relationship between neonatal BI and ND outcome has not been established. OBJECTIVES:This study sought to determine the association between peri-operative BI and ND outcomes in infants with single ventricle physiology (SVP) and d-transposition of the great arteries (d-TGA). METHODS:Term newborns with d-TGA and SVP had pre-operative and post-operative brain magnetic resonance imaging and ND outcomes assessed at 12 and 30months with the Bayley Scales of Infant Development-II. BI was categorized by the brain injury severity score and WMI was quantified by volumetric analysis. RESULTS:A total of 104 infants had follow-up at 12months and 70 had follow-up at 30months. At 12months, only clinical variables were associated with ND outcome. At 30months, subjects with moderate-to-severe WMI had significantly lower Psychomotor Development Index (PDI) scores (13 points lower) as compared with those with none or minimal WMI for d-TGA and SVP (p=0.03 and p=0.05, respectively) after adjusting for various factors. Quantitative WMI volume was likewise associated. Stroke was not associated with outcome. The Bland-Altman limits of agreement for PDI scores at 12 and 30months were wide (-40.3 to 31.2) across the range of mean PDI values. CONCLUSIONS:Increasing burden of WMI is associated with worse motor outcomes at 30months for infants with criticalcongenital heart disease, whereas no adverse association was seen between small strokes and outcome. Theseresults support the utility of neonatal brain magnetic resonance imaging in this population to aid in predictinglateroutcomes and the importance of ND follow-up beyond 1 year of age.

Preterm birth is associated with brain injury and altered cognitive development. However, the consequences of extrauterine development are not clearly distinguished from perinatal brain injury. Therefore, we characterized cortical growth patterns from 30 to 46 postmenstrual weeks (PMW) in 27 preterm neonates (25-32 PMW at birth) without detectable brain injury on magnetic resonance imaging. We introduce surface-based morphometric descriptors that quantify radial (thickness) and tangential (area) change rates. Within a tensor-based morphometry framework, we use a temporally weighted formulation of regression to simultaneously model local age-related changes in cortical gray matter (GM) and underlying white matter (WM) mapped onto the cortical surface. The spatiotemporal pattern of GM and WM development corresponded to the expected gyrification time course of primary sulcal deepening and branching. In primary gyri, surface area and thickness rates were below average along sulcal pits and above average on gyral banks and crests in both GM and WM. Above average surface area rates in GM corresponded to emergence of secondary and tertiary folds. These findings map the development of neonatal cortical morphometry in the context of extrauterine brain development using a novel approach. Future studies may compare this developmental trajectory to preterm populations with brain injury. Hum Brain Mapp 38:4322-4336, 2017. © 2017 Wiley Periodicals, Inc.

Aim: To determine the association between lowest plasma magnesium concentration and brain metabolism, and whether magnetic resonance imaging brain injury patterns moderated the association in hypoxic-ischemic encephalopathy. Methods: In 131 early (day-of-life 3) and 65 late (day-of-life 10) scans of term encephalopathic infants born between 2004 and 2012, we examined the association of lowest plasma magnesium (until day-of-life 3) on basal ganglia and white matter peak metabolite ratios on magnetic resonance spectroscopy independent of covariates, stratified by the predominant patterns of injury (normal, basal nuclei/total, watershed, multifocal) using multiple linear regression. Results: Lowest plasma magnesium was associated with lower white matter N-acetyl-aspartate/choline in the multifocal pattern on early scan (regression-coefficient, β: 0.13; 95% CI: 0.04, 0.22) and in the basal nuclei/total pattern on late scan (β: 0.08; 95% CI: 0.02, 0.15), and was negatively associated with basal ganglia lactate/N-acetyl-aspartate (β: −0.16; 95% CI: −0.05, −0.28) and lactate/choline (β: −0.1; 95% CI: −0.03, −0.17) ratio in the basal nuclei/total pattern on late scan independent of hypomagnesaemia correction, cooling and postmenstrual age at scan. Lowest plasma magnesium was not associated with metabolite ratios in other brain injury patterns. Conclusion: In infants with hypoxic-ischaemic encephalopathy, predominant patterns of brain injury moderated the association between lowest plasma magnesium in the first three days of life and impaired brain metabolism.

Objective Very preterm-born neonates (24–32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic–sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. Methods A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development–III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries. Results Total midazolam dose predicted decreased hippocampal volumes (β = −1.8, p 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = −0.31, p = 0.003), midazolam dose (β = −0.27, p = 0.03), and surgery (β = −8.32, p = 0.04). Interpretation Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned. Ann Neurol 2016;79:548–559

Objectives To evaluate whether the number of postnatal infections is associated with abnormal white matter maturation and poorer motor neurodevelopmental outcomes at 36 months of corrected age. Study design A prospective longitudinal cohort study was undertaken of 219 newborns born preterm at 24-32 weeks of gestational age recruited between 2006 and 2013 with magnetic resonance imaging of the brain both early in life and at term-equivalent age. Postnatal infection was defined as any clinical infection or positive culture ≥72 hours after birth. White matter maturation was assessed by magnetic resonance spectroscopic imaging, magnetic resonance diffusion tensor imaging, and tract-based spatial statistics. Neurodevelopmental outcomes were assessed in 175 (82% of survivors) infants with Bayley Scales of Infant and Toddler Development-III composite scores and Peabody Developmental Motor Scales at 35 months of corrected age (IQR 34-37 months). Infection groups were compared via the Fisher exact test, Kruskal–Wallis test, and generalized estimating equations. Results Of 219 neonates born preterm (median gestational age 27.9 weeks), 109 (50%) had no postnatal infection, 83 (38%) had 1 or 2 infections, and 27 (12%) had ≥3 infections. Infants with postnatal infections had more cerebellar hemorrhage. Infants with ≥3 infections had lower N-acetylaspartate/choline in the white matter and basal ganglia regions, lower fractional anisotropy in the posterior limb of the internal capsule, and poorer maturation of the corpus callosum, optic radiations, and posterior limb of the internal capsule on tract-based spatial statistics analysis as well as poorer Bayley Scales of Infant and Toddler Development-III (P = .02) and Peabody Developmental Motor Scales, Second Edition, motor scores (P Conclusions In newborns born preterm, ≥3 postnatal infections predict impaired development of the motor pathways and poorer motor outcomes in early childhood.

In cooled newborns with encephalopathy, although late magnetic resonance imaging (MRI) scan (10-14 days of age) is reliable in predicting long-term outcome, it is unknown whether early scan (3-6 days of life) is. We compared the predominant pattern and extent of lesion between early and late MRI in 89 term neonates with neonatal encephalopathy. Forty-three neonates (48%) were cooled. The predominant pattern of lesions and the extent of lesion in the watershed region agreed near perfectly in noncooled (kappa = 0.94; k = 0.88) and cooled (k = 0.89; k = 0.87) infants respectively. There was perfect agreement in the extent of lesion in the basal nuclei in noncooled infants (k = 0.83) and excellent agreement in cooled infants (k = 0.67). Changes in extent of lesions on late MRI occurred in 19 of 89 infants, with higher risk in infants with hypoglycemia and moderate-severe lesions in basal nuclei. In most term neonates with neonatal encephalopathy, early MRI (relative to late scan) robustly predicts the predominant pattern and extent of injury.

Introduction The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. Methods First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. Results The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice's Kappa > 0.79 and Euclidean distance, Highlights • We develop a MAGeT-Brain based automatic protocol to segment hippocampus in preterm neonates. • MAGeT-Brain can accurately segment hippocampus in preterm neonates, even at early-in-life. • Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images. • Smaller hippocampal volumes are associated with earlier birth in preterm neonates.

Objective: To identify clinical risk factors for punctate white matter lesions (PWML) on early magnetic resonance imaging (MRI) in 2 cohorts of newborns born extremely preterm in different neonatal centers. Study design: A total of 250 newborns born preterm at less than 28 weeks of gestation (mean 26.4 ± 1.1 weeks) with an early MRI were identified from 2 neonatal centers, in Vancouver, Canada (cohort A, n = 100) and Utrecht, the Netherlands (cohort B, n = 150). Cohort A was imaged as part of a prospective research study and cohort B was imaged as part of routine clinical care. PWML were defined as cluster type foci of hyperintensity on T1-weighted imaging and were identified at a mean postmenstrual age of 31.1 (±1.9) weeks. Multivariable analysis was used to identify clinical factors predictive of PWML. Results: Cluster type PWML were found in 47 newborns born extremely preterm (18.8%) and were more common in cohort A (32%) than in cohort B (10%). Newborns in cohort A generally were sicker than those in cohort B. Multivariable analyses revealed that greater birth weight (B = 0.002; P

Cranial fasciitis is a fibroblastic lesion found in the cranium of children three weeks to six years of age. It most commonly manifests as a solitary, rapid growing mass on the scalp with frequent involvement of underlying bone and occasional intracranial expansion. Patients with cranial fasciitis may present with a wide range of associated symptoms. Otologic symptoms such as otalgia, otorrhea, hearing loss and middle ear effusion are not frequently encountered. We present a case of cranial fasciitis with intracranial involvement and associated otologic symptoms in a four year old boy with subsequent follow up 14 years later.

Neonatal encephalopathy is a neurological emergency with heterogeneous etiologies and several management challenges. Neonatal encephalopathy of hypoxic-ischemic origin is associated with high rate of neonatal morbidity and mortality, and the long-term neurodevelopmental outcome of survivors with moderate to severe encephalopathy is poor. Magnetic resonance imaging now provides new insights on the diagnosis and prognosis of this condition. Typical patterns of brain injury have been recognized and in contemporary cohorts of newborns these patterns reflect different risk factors and clinical presentation, as well as specific patterns of neurodevelopmental outcome. Magnetic resonance spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging are advanced MR techniques that are increasingly used in the assessment of encephalopathic newborns, providing innovative perspectives on neonatal brain metabolism, microstructure, and connectivity. These techniques have been particularly helpful in elucidating the unique time course of neonatal brain injury and in providing quantitative biomarkers for prognostication. To better refine the prognostic value of these new imaging tools, standardization of protocols, imaging modalities and scan timing are needed across centers. It is hoped that these techniques will permit earlier identification of newborns at risk of neurodevelopmental impairment and complement ongoing trials of emerging therapies such as hypothermia and novel pharmacological agents with neuroprotective properties.

BACKGROUND: Very preterm infants (born 24–32 weeks’ gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS: Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5–7.7). T1- and T2-weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children–IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS: Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS: Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ.

Objective There is considerable variability in anticoagulation use in neonates with transposition of the great arteries (TGA) and single ventricle physiology (SVP) for secondary stroke prevention and primary cardiovascular indications. Leveraging cross-center differences in anticoagulation use, we compared the risk of new postoperative brain injury in neonates with TGA and SVP treated with anticoagulation relative to untreated neonates. Methods Two-center observational cohort study of 118 term-born neonates with TGA (n = 83) and SVP (n = 35), undergoing cardiopulmonary bypass surgery and pre- and postoperative brain magnetic resonance imaging. Anticoagulation and antiplatelet therapy details were obtained. Magnetic resonance images were scored for stroke, white matter injury, and hemorrhage. New postoperative injury was compared between neonates with and without anticoagulation for the 2-center cohort, and subsequently stratified by cardiac lesion type and anticoagulation indication. Results Thirty-six out of 118 neonates (29%) received anticoagulation: 11 (30%) for preoperative stroke, 20 (56%) for preoperative peripheral/intracardiac thrombus, and 5 (14%) for Blalock-Taussig shunt. Five out of 36 neonates (14%) treated with anticoagulation also received antiplatelet therapy. Although no differences were identified for the 2-center cohort or for neonates with TGA separately, significantly more new postoperative parenchymal brain injury (P = .04), particularly stroke, was found in SVP neonates with compared to without anticoagulation (31% vs 5%). In neonates who experienced preoperative stroke, new subdural hemorrhage (36% vs 0%) was more frequent in neonates treated with anticoagulation therapy compared with those without anticoagulation therapy. Conclusions In our cohort of neonates with TGA and SVP, anticoagulation for preoperative stroke, preoperative thrombus, and/or Blalock-Taussig shunt did not have the anticipated benefit of preventing new perioperative brain injury. These findings indicate the critical need for rigorous randomized trials on the safety and effectiveness of anticoagulation therapy in this population.

BACKGROUND: To evaluate the predominant pattern of brain injury and the anatomic areas of injury in children with infantile spasms following neonatal hypoxic-ischemic encephalopathy. METHODS: A nested case-control study of infantile spasms in children with term neonatal hypoxic-ischemic encephalopathy was performed. All patients had T1/T2-weighted magnetic resonance imaging with diffusion-weighted imaging performed on the third day of life. Using a validated scoring system, the magnetic resonance imaging was classified as: normal, watershed, basal ganglia/thalamus, total, or focal-multifocal. Two study investigators scored additional anatomic areas of injury (cortical extent, levels of the brainstem, hypothalamus) on T1/T2-weighted magnetic resonance imaging and diffusion-weighted imaging blinded to the outcome. The predominant pattern of brain injury and anatomic areas of injury were compared between patients who developed infantile spasms and randomly selected controls. RESULTS: Eight patients who developed infantile spasms were identified among a cohort of 176 term newborns with hypoxic-ischemic encephalopathy (4.5%). There were no significant differences in the perinatal and neonatal course between newborns who developed infantile spasms and controls who did not. The development of infantile spasms after neonatal hypoxic-ischemic encephalopathy was significantly associated with basal ganglia/thalamus and total brain injury (P ¼ 0.001), extent of cortical injury greater than 50% (odds ratio ¼ 11.7, 95% confidence interval ¼ 1.1-158.5, P ¼ 0.01), injury to the midbrain (odds ratio ¼ 13, 95% confidence interval ¼ 1.3-172, P ¼ 0.007) and hypothalamic abnormalities (P ¼ 0.01). CONCLUSIONS: The development of infantile spasms after hypoxic-ischemic encephalopathy is associated with injury to the basal ganglia and thalami on neonatal magnetic resonance imaging, particularly when extensive cortical injury and/or injury to the midbrain is present.

Brain injury in term neonatal hypoxic-ischemic encephalopathy (HIE) emerges on magnetic resonance imaging (MRI) by day 3. This study aimed to address the relationship of MRI, diffusion tensor imaging (DTI), and MR spectroscopic imaging (MRSI) findings on days 1 and 3 in a prospective cohort of term newborns with HIE.A total of 24 term newborns with HIE were prospectively studied with MRI on days 1 and 3; 19 were imaged with DTI and MRSI on days 1 and 3. MRI was assessed using validated scores. The relationship between MRI, DTI, and MRSI values on days 1 and 3 was determined using linear regression for repeated measures.Conventional MRI showed a complex variation of findings from day 1 to 3. In gray matter, mean diffusivity (Dav) and metabolite ratios measured on day 1 were predictive of values on day 3 (all P ≤ 0.04). In white matter, Dav, fractional anisotropy (FA), and N-acetylaspartate (NAA)/choline on days 1 and 3 were strongly related (all P ≤ 0.003). Hypothermia appeared to attenuate the severity and progression of brain injury in the six treated newborns.In term newborns with HIE, quantitative MR values on days 1 and 3 are strongly associated, providing an objective measure of injury before qualitative images.

To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.Infants born ≤ 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis.

Objective To determine whether severe retinopathy of prematurity (ROP) is associated with (1) abnormal white matter maturation and (2) neurodevelopmental outcomes at 18 months’ corrected age (CA) compared with neonates without severe ROP. Design We conducted a prospective longitudinal cohort of extremely preterm neonates born 24–28 weeks’ gestational age recruited between 2006 and 2013 with brain MRIs obtained both early in life and at term-equivalent age. Severe ROP was defined as ROP treated with retinal laser photocoagulation. Using diffusion tensor imaging and tract-based spatial statistics (TBSS), white matter maturation was assessed by mean fractional anisotropy (FA) in seven predefined regions of interest. Neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development-III (Bayley-III) composite scores at 18 months’ CA. Subjects were compared using Fisher’s exact, Kruskal-Wallis and generalised estimating equations. Setting Families were recruited from the neonatal intensive care unit at BC Women’s Hospital. Patients Of 98 extremely preterm neonates (median: 26.0 weeks) assessed locally for ROP, 19 (19%) had severe ROP and 83 (85%) were assessed at 18 months’ CA. Results Severe ROP was associated with lower FA in the posterior white matter, and with decreased measures of brain maturation in the optic radiations, posterior limb of the internal capsule (PLIC) and external capsule on TBSS. Bayley-III cognitive and motor scores were lower in infants with severe ROP. Conclusions Severe ROP is associated with maturational delay in the optic radiations, PLIC, external capsule and posterior white matter, housing the primary visual and motor pathways, and is associated with poorer cognitive and motor outcomes at 18 months’ CA.

Aim To characterize corpus callosum development in neonates born very preterm from early in life to term-equivalent age and its relationship with neurodevelopmental outcome at 18 months corrected age. Method In a prospective cohort of 193 neonates born preterm, 24 to 32 weeks' gestation, we used magnetic resonance imaging and diffusion tensor imaging acquired early in life (n=193) and at term-equivalent age (n=159) to measure corpus callosum development: mid-sagittal area (including corpus callosum subdivisions) and length, and fractional anisotropy from the genu and splenium. We examined the association of (1) intraventricular haemorrhage (IVH) and white matter injury (WMI) severity, and (2) neurodevelopmental outcome at 18 months corrected age with corpus callosum development. Results Severe WMI and severe IVH were strongly associated with reduced corpus callosum area (both p

Many studies using T1 magnetic resonance imaging (MRI) data have found associations between changes in global metrics (e.g. volume) of brain structures and preterm birth. In this work, we use the surface displacement feature extracted from the deformations of the surface models of the third ventricle, fourth ventricle and brainstem to capture the variation in shape in these structures at 8 years of age that may be due to differences in the trajectory of brain development as a result of very preterm birth (24-32 weeks gestation). Understanding the spatial patterns of shape alterations in these structures in children who were born very preterm as compared to those who were born at full term may lead to better insights into mechanisms of differing brain development between these two groups. The T1 MRI data for the brain was acquired from children born full term (FT, n=14, 8 males) and preterm (PT, n=51, 22 males) at age 8-years. Accurate segmentation labels for these structures were obtained via a multi-template fusion based segmentation method. A high dimensional non-rigid registration algorithm was utilized to register the target segmentation labels to a set of segmentation labels defined on an average-template. The surface displacement data for the brainstem and the third ventricle were found to be significantly different (p < 0.05) between the PT and FT groups. Further, spatially localized clusters with inward and outward deformation were found to be associated with lower gestational age. The results from this study present a shape analysis method for pediatric MRI data and reveal shape changes that may be due to preterm birth.

Objective:To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes.Methods:Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed.Results:WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes (p = 0.001). Lobar regional analysis revealed that greater WMI volumes in frontal, parietal, and temporal lobes have adverse motor outcomes (all, p < 0.05), but only frontal WMI volumes predicted adverse cognitive outcomes (p = 0.002). To account for lesion location and volume, voxel-wise odds ratio (OR) maps demonstrate that frontal lobe lesions predict adverse cognitive and language development, with maximum odds ratios (ORs) of 78.9 and 17.5, respectively, while adverse motor outcomes are predicted by widespread injury, with maximum OR of 63.8.Conclusions:The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern.

International audience; Accurate automated tissue segmentation of premature neonatal magnetic resonance images is a crucial task for quantification of brain injury and its impact on early postnatal growth and later cognitive development. In such studies it is common for scans to be acquired shortly after birth or later during the hospital stay and therefore occur at arbitrary gestational ages during a period of rapid developmental change. It is important to be able to segment any of these scans with comparable accuracy. Previous work on brain tissue segmentation in premature neonates has focused on segmentation at specific ages. Here we look at solving the more general problem using adaptations of age specific atlas based methods and evaluate this using a unique manually traced database of high resolution images spanning 20 gestational weeks of development. We examine the complimentary strengths of age specific atlas-based Expectation-Maximization approaches and patch-based methods for this problem and explore the development of two new hybrid techniques, patch-based augmentation of Expectation-Maximization with weighted fusion and a spatial variability constrained patch search. The former approach seeks to combine the advantages of both atlas- and patch-based methods by learning from the performance of the two techniques across the brain anatomy at different developmental ages, while the latter technique aims to use anatomical variability maps learnt from atlas training data to locally constrain the patch-based search range. The proposed approaches were evaluated using leave-one-out cross-validation. Compared with the conventional age specific atlas-based segmentation and direct patch based segmentation, both new approaches demonstrate improved accuracy in the automated labeling of cortical gray matter, white matter, ventricles and sulcal cortical-spinal fluid regions, while maintaining comparable results in deep gray matter.

Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.Infants born very preterm (N=86; 24-32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery.After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β=-0.0002, p=0.028) and reduced subcortical gray matter NAA/choline (β=-0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.Early procedural pain in very preterm infants may contribute to impaired brain development.

Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and metabolic brain development in premature newborns. In 34/117 newborns studied, clinical signs were accompanied by positive cultures whereas 17 had clinical signs of sepsis alone. White matter injury (WMI) was identified in 34 newborns. In multivariate regression models, infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (DAV), and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection. These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain development. These abnormalities extend beyond brain injuries apparent with conventional magnetic resonance injury (MRI). 117 preterm newborns (24–32 wk gestation) were studied prospectively at a median of 32.0 and 40.3 wk ostmenstrual age with MRI (WMI, hemorrhage), magnetic resonance (MR) spectroscopy (metabolism), and diffusion tensor imaging (microstructure). Newborns were categorized as having “no infection,” “clinical infection,” or “positive-culture infection.” We compared brain injuries as well as metabolic and microstructural development across these infection groups.

Resting cortical activity is characterized by a distinct spectral peak in the alpha frequency range. Slowing of this oscillatory peak toward the upper theta-band has been associated with a variety of neurological and neuropsychiatric conditions, and has been attributed to altered thalamocortical dynamics. Children born very preterm exhibit altered development of thalamocortical systems. To test the hypothesis that peak oscillatory frequency is slowed in children born very preterm, we recorded resting magnetoencephalography (MEG) from school age children born very preterm (≤32 weeks gestation) without major intellectual or neurological impairment and age-matched full term controls. Very preterm children exhibit a slowing of peak frequency toward the theta-band over bilateral frontal cortex, together with reduced alpha-band power over bilateral frontal and temporal cortex, suggesting that mildly dysrhythmic thalamocortical interactions may contribute to altered spontaneous cortical activity in children born very preterm.

Objective Preoperative brain injury, particularly stroke and white matter injury, is common in neonates with congenital heart disease. The objective of this study was to determine the risk of hemorrhage or extension of preoperative brain injury with cardiac surgery. Methods This dual-center prospective cohort study recruited 92 term neonates, 62 with transposition of the great arteries and 30 with single ventricle physiology, from 2 tertiary referral centers. Neonates underwent brain magnetic resonance imaging scans before and after cardiac surgery. Results Brain injury was identified in 40 (43%) neonates on the preoperative magnetic resonance imaging scan (median 5 days after birth): stroke in 23, white matter injury in 21, and intraventricular hemorrhage in 7. None of the brain lesions presented clinically with overt signs or seizures. Preoperative brain injury was associated with balloon atrial septostomy ( P = .003) and lowest arterial oxygen saturation ( P = .007); in a multivariable model, only the effect of balloon atrial septostomy remained significant when adjusting for lowest arterial oxygen saturation. On postoperative magnetic resonance imaging in 78 neonates (median 21 days after birth), none of the preoperative lesions showed evidence of extension or hemorrhagic transformation (0/40 [95% confidence interval: 0%–7%]). The presence of preoperative brain injury was not a significant risk factor for acquiring new injury on postoperative magnetic resonance imaging ( P = .8). Conclusions Clinically silent brain injuries identified preoperatively in neonates with congenital heart disease, including stroke, have a low risk of progression with surgery and cardiopulmonary bypass and should therefore not delay clinically indicated cardiac surgery. In this multicenter cohort, balloon atrial septostomy remains an important risk factor for preoperative brain injury, particularly stroke.

X-linked mental retardation (XLMR) affects 1-2/1,000 males and accounts for approximately 10% of all mental retardation (MR). We have ascertained a syndromic form of XLMR segregating within a five-generation family with seven affected males. Prominent characteristics include mild to severe MR, cortical malformation, microcephaly, seizures, thin build with distinct facial features including a long and thin face, epicanthic folds, almond-shaped eyes, upslanting palpebral fissures and micrognathia and behavioral problems. Carrier females have normal physical appearance and intelligence. This combination of features is unreported and distinct from Lujan-Fryns syndrome, Snyder-Robinson syndrome, and zinc finger DHHC domain-containing 9-associated MR. We propose the name of this new syndrome to be CK syndrome.

Objective [ ] The association of chorioamnionitis and non-cystic white matter injury, a common brain injury in premature newborns, remains controversial. Our objectives were to determine the association of chorioamnionitis and postnatal risk factors with white matter injury, and the effects of chorioamnionitis on early brain development, using advanced MR imaging. Methods [ ] Ninety-two preterm newborns (24-32 weeks gestation) were studied at a median age of 31.9 weeks and again at 40.3 weeks gestation. Histopathological chorioamnionitis and white matter injury were scored using validated systems. Measures of brain metabolism (N-acetylaspartate/choline and lactate/choline) on magnetic resonance spectroscopy, and microstructure (average diffusivity and fractional anisotropy) on diffusion tensor imaging were calculated from predefined brain regions. Results [ ] Thirty-one newborns (34%) were exposed to histopathological chorioamnionitis, and 26 (28%) had white matter injury. Histopathological chorioamnionitis was not associated with an increased risk of white matter injury (relative risk: 1.2; P=0.6). Newborns with postnatal infections and hypotension requiring therapy were at higher risk of white matter injury (P0.1). In contrast, white matter injury was associated with lower N-acetylaspartate/choline (–8.9%; P=0.009) and lower white matter fractional anisotropy (–11.9%; P=0.01). Interpretation [ ] Histopathological chorioamnionitis does not appear to be associated with an increased risk of white matter injury on magnetic resonance imaging or with abnormalities of brain development. In contrast, postnatal infections and hypotension are associated with an increased risk of white matter injury in the premature newborn. Final published version [ ] Ann Neurol. 2009 Aug;66(2):155-64. URL: http://www3.interscience.wiley.com/journal/76507645/home

Neonatal encephalopathy is associated with a high risk of morbidity and mortality in the neonatal period and of long-term neurodevelopmental disability in survivors. Advanced magnetic resonance techniques now play a major role in the clinical care of newborns with encephalopathy and in research addressing this important condition. From conventional magnetic resonance imaging, typical patterns of injury have been defined in neonatal encephalopathy. When applied in contemporary cohorts of newborns with encephalopathy, the patterns of brain injury on magnetic resonance imaging distinguish risk factors, clinical presentation, and risk of abnormal outcome. Advanced magnetic resonance techniques such as magnetic resonance spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging provide novel perspectives on neonatal brain metabolism, microstructure, and connectivity. With the application of these imaging tools, it is increasingly apparent that brain injury commonly occurs at or near the time of birth and evolves over the first weeks of life. These observations have complemented findings from trials of emerging strategies of brain protection, such as hypothermia. Application of these advanced magnetic resonance techniques may enable the earliest possible identification of newborns at risk of neurodevelopmental impairment, thereby ensuring appropriate follow-up with rehabilitation and psychoeducational resources.

Detailed neurological, speech and language, psychological, and neuroimaging studies were carried out in eight children with the diagnosis of congenital ocular motor apraxia. The neurological examination showed clinical evidence of cerebellar vermis abnormality (hypotonia and truncal ataxia) in all cases. Neuroimaging studies suggested that the site of neuropathological disturbance of congenital ocular motor apraxia was the inferior vermis. Half of the subjects had associated speech apraxia. The most likely location of brain disturbance, which was responsible for the speech apraxia, was also an as yet undefined area of the vermis. Psychological testing consistently revealed visual-spatial difficulties. These may have been secondary to cerebellar pathology or to developmentally inappropriate sensory input caused by the abnormal saccades. Children with speech apraxia appear to be slightly more affected neurologically than those with normal speech.

The treatment of symptomatic Chiari II malformations typically involves multilevel cervical laminectomies in very young children. These patients are at significant risk of cervical instability. The purpose of this study was to determine the incidence and significance of cervical instability after multilevel cervical laminectomies in a cohort of patients decompressed for Chiari II malformation.Postoperative dynamic lateral cervical spine radiographs were obtained on pediatric patients who had multilevel cervical laminectomies for symptomatic Chiari II malformations. Postoperative cervical spine instability was determined radiographically using published criteria. Clinical instability and need for cervical fusion were also assessed.Nine patients met inclusion criteria for the study. Five of the nine patients (56%) showed evidence of radiographic instability of their cervical spines following surgery for their Chiari II malformations, according to the criteria used. No patient showed evidence of clinical instability or required cervical fusion.Radiographic evidence of cervical spine instability following multilevel cervical laminectomies for Chiari II is common but may be of minimal clinical significance. The reason for the lack of clinical instability in what might be considered high-risk patients is not understood.

OBJECTIVE. Our objective was to identify clinical predictors of progressive white matter injury. METHODS. We evaluated 133 infants of RESULTS. Twelve neonates (9.0%) had progressive white matter injury. In the unadjusted analysis of 10 newborns without Candida meningoencephalitis, recurrent culture-positive postnatal infection and chronic lung disease were associated with progressive white matter injury. Exposure to multiple episodes of culture-positive infection significantly increased the risk of progressive white matter injury. Of the 11 neonates with >1 infection, 36.4% (4 infants) had progressive injury, compared with 5.0% (6 infants) of those with ≤1 infection. Of the 35 infants with chronic lung disease, 17.1% (6 infants) had progressive injury, compared with 4.3% (4 infants) of those without chronic lung disease. After adjustment for gestational age at birth, the association between infection and white matter injury persisted, whereas chronic lung disease was no longer a statistically significant risk factor. CONCLUSIONS. Recurrent postnatal infection is an important risk factor for progressive white matter injury in premature infants. This is consistent with emerging evidence that white matter injury is attributable to oligodendrocyte precursor susceptibility to inflammation, hypoxia, and ischemia.

BACKGROUND AND PURPOSE: Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age. MATERIALS AND METHODS: Of 180 neonates (born at 24–32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed. RESULTS: Tract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30–33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37–41 weeks), tract-based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at

Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome.A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries.Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04).Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.

We introduce the STEAM DTI analysis engine: a whole brain voxel-based analysis technique for the examination of diffusion tensor images (DTIs). Our STEAM analysis technique consists of two parts. First, we introduce a collection of statistical templates that represent the distribution of DTIs for a normative population. These templates include various diffusion measures from the full tensor, to fractional anisotropy, to 12 other tensor features. Second, we propose a voxel-based analysis (VBA) pipeline that is reliable enough to identify areas in individual DTI scans that differ significantly from the normative group represented in the STEAM statistical templates. We identify and justify choices in the VBA pipeline relating to multiple comparison correction, image smoothing, and dealing with non-normally distributed data. Finally, we provide a proof of concept for the utility of STEAM on a cohort of 134 very preterm infants. We generated templates from scans of 55 very preterm infants whose T1 MRI scans show no abnormalities and who have normal neurodevelopmental outcome. The remaining 79 infants were then compared to the templates using our VBA technique. We show: (a) that our statistical templates display the white matter development expected over the modeled time period, and (b) that our VBA results detect abnormalities in the diffusion measurements that relate significantly with both the presence of white matter lesions and with neurodevelopmental outcomes at 18months. Most notably, we show that STEAM produces personalized results while also being able to highlight abnormalities across the whole brain and at the scale of individual voxels. While we show the value of STEAM on DTI scans from a preterm infant cohort, STEAM can be equally applied to other cohorts as well. To facilitate this whole-brain personalized DTI analysis, we made STEAM publicly available at http://www.sfu.ca/bgb2/steam.

We propose a method to identify preterm infants at highest risk of adverse motor function identified at 18 months of age using connectome features from a diffusion tensor image DTI acquired shortly after birth. For each full-brain DTI, a connectome is constructed and network features are extracted. After further reducing the dimensionality of the feature vector via PCA, SVM is used to discriminate between normal and abnormal motor scores. We further introduce a novel method to produce realistic synthetic training data in order to reduce the effects of class imbalance. Our method is tested on a dataset of 168 DTIs of 115 very preterm infants, scanned between 27 and 45 weeks post-menstrual age. We show that using our synthesized training data can consistently improve classification accuracy while setting a baseline for this challenging prediction problem. This work presents the first image analysis approach to predicting impairment in motor function in preterm-born infants.

Trichothiodystrophy is a rare neuroectodermal disorder of autosomal recessive inheritance that is characterized by brittle hair, nail dysplasia, ichthyosis, mental retardation, and gonadal failure. We describe a female patient whose cranial MRI revealed almost total lack of myelination in the supratentorial white matter, which is similar to the previously described cases. In addition, there was progressive cerebellar and cerebral atrophy, which has not been well documented in association with trichothiodystrophy.

Computerized tomography (CT) of the brain was performed in 10 of 11 consecutive infants with neonatal lupus erythematosus (NLE) (five boys and six girls). Ten of the 11 infants had brain neurosonography. Nine of 10 infants had abnormal CT scans. There was diffuse, markedly reduced attenuation of the cerebral white matter in four infants studied in the first week of life, and also in an infant 5 weeks of age. Patchy reduced subcortical white matter attenuation was observed in another 5-week-old infant. Basal ganglia calcifications were present in two infants at 2 months of age, one of whom also had mild ventriculomegaly. A patient with macrocephaly studied at 4 months of age had enlarged ventricles and subarachnoid spaces consistent with benign macrocephaly of infancy. Cerebral ultrasound examination was abnormal in all five infants studied in the first week of life and in one infant at 2 months of age. Findings included subependymal cysts (4), echogenic white matter (3), and echogenic lenticulostriate vessels (3). Apart from one case of macrocephaly, there was no clinical evidence of neurologic disease and the subsequent development of these infants has been normal. Subclinical central nervous system (CNS) disease in NLE is likely to be a transient phenomenon that resolves as maternal antibodies are cleared from the infant's circulation. It is important to be aware of these neuroimaging abnormalities to avoid misdiagnosis of congenital viral infection in a newborn with multisystem NLE. The potential for neurologic sequelae is uncertain.

Prise en charge de l'astrocytome du chiasma optique/de l'hypothalamus chez l'enfant. Objectif: La prise en charge des gliomes du chiasma optique est controversee, en partie parce qu'on ne fait pas de distinction entre les tumeurs impliquant seulement le chiasma optique (tumeurs chiasmatiques) et celles qui impliquent egalement l'hypothalamus (tumeurs chiasmatiques/hypothalamiques). Les objectifs de cette etude etaient: (i) d'analyser separement l'issue des tumeurs chiasmatiques et chiasmatiques/hypothalamiques: et (ii) de determiner la pertinence de recommander la resection chirurgicale radicale des tumeurs chiasmatiques/hypothalamiques. Methodes: Nous avons procede a une revue retrospective des dossiers de patients porteurs de tumeurs nouvellement diagnostiquees impliquant le chiasma optique entre 1982 et 1996 au Children's Hospital de la Colombie Britannique. Resultats: L'etude porte sur 32 patients de moins de 16 ans, 14 presentant un astrocytome chiasmatique et 18 un astrocytome chiasmatique/hypothalamique. La duree moyenne du suivi etait de 5,8 ans et 6,3 ans respectivement. Dix des patients porteurs de tumeurs chiasmatiques etaient atteints de neurofibromatose de type I alors qu'aucun des patients porteurs de tumeurs chiasmatiques/hypothalamiques n'en etaient atteints. La conduite pour 13 des 14 tumeurs chiasmatiques a ete l'observation seulement et aucune n'a necessite une intervention a cause de la progression de la tumeur, Quant aux patients atteints de tumeurs chiasmatiques/hypothalamiques, huit ont subi une resection subtotale (resection de plus de 95%), six ont subi une resection partielle (de 50 a 95%, trois ont subi une resection limitee (de moins de 50%) et un n'a pas ete opere. Il y a eu moins de complications associees aux resections limitees, surtout quant a la dysfonction hypothalamique. Il n'existait pas de correlation entre l'etendue de la resection (subtotale, partielle ou limitee) et le moment de la recidive (en moyenne 18 mois). Conclusions: Les tumeurs chiasmatiques et chiasmatiques/hypothalamiques sont des entites differentes qui devraient etre considerees separement dans les etudes. Pour les tumeurs chiasmatiques/hypothalamiques, il y avait davantage de morbidite, sans prolongation du temps de remission, quand on compare la resection radicale a la resection limitee Si on a recours a la chirurgie, il peut etre approprie de faire une intervention dont le but n'est que de fournir un diagnostic anatomopathologique et de decomprimer l'appareil optique et/ou le systeme ventriculaire.

Objective To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age. Study design Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T 1 -weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated. Results Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration. Conclusions In very preterm children, exposure to painful procedures, as well as additional neonatal risk factors such as infection, were associated with reduced cerebellar volumes in specific subregions and poorer outcomes at school age.